Decreased concentrations of monoamine neurotransmitters, such as serotonin (also known as 5-hydroxytryptamine or 5-HT), noradrenaline (norepinephrine), and dopamine, are implicated in a number of disorders of the central or peripheral nervous system. These disorders include depression, eating disorders, schizophrenia, inflammatory bowel disorders, pain, addiction disorders, urinary incontinence, dementia, Alzheimer's, memory loss, Parkinsonism, anxiety, attention-deficit disorder, social phobia, obsessive compulsive disorder, substance abuse and withdrawal, cognitive disorders, fibromyalgia and sleep disorders. These neurotransmitters travel from the terminal of a neuron across a small gap (i.e., the synaptic cleft) and bind to receptor molecules on the surface of a second neuron. This binding elicits intracellular changes that initiate or activate a response or change in the postsynaptic neuron. Inactivation occurs primarily by transport (i.e., reuptake) of the neurotransmitter back into the presynaptic neuron. Enhancing the amount of one or more of these monoamines has been shown to have utility in the treatment of disorders such as depression, anxiety, neuropathic pain, fibromyalgia, urinary incontinence and attention deficit hyperactivity disorder (ADHD). One advantageous method to increase the amount of a monoamine or monoamines is by administering a re-uptake inhibitor which has a particular selectivity/affinity to one or more monoamine transporters.
Selective serotonin re-uptake inhibitors (SSRIs) function by inhibiting the reuptake of serotonin by afferent neurons. SSRIs well known in the art include sertraline (Zoloft®), fluoxetine (Prozac®) and paroxetine (Paxil®). Selective noradrenaline (or norepinephrine) re-uptake inhibitors function by increasing noradrenaline levels and include drugs known in the art including reboxetine (Edronax®), atomoxetine (Strattera®), and buproprion (Wellbutrin®). Dual serotonin-noradrenaline re-uptake inhibitors (SNRIs) which inhibit the reuptake of both serotonin and norepinephrine include venlafaxine (Effexor®), duloxetine (Cymbalta®), milnacipran and imipramine (Tofranil®).
While significant strides have been made in this field, there remains a need in the art for effective small molecule monoamine re-uptake inhibitors. These inhibitors may advantageously possess characteristics such as enhanced selectively toward one or more monoamine transporters, enhanced pharmacokinetic properties (such as half-life, bioavailability, and minimal interaction with liver enzymes such as the cytochrome P450 family), and/or enhanced potency. There is also a need for pharmaceutical compositions containing such monoamine re-uptake inhibitors, as well as methods relating to the use thereof to treat, for example, conditions caused by low concentrations of a monoamine or monoamines. The present invention fulfills these needs, and provides other related advantages.